I. Field of the Invention
The present invention relates to a pharmaceutical composition for treating bone disorders such as osteoporosis or hypercalcemia of patients suffering from malignant tumors. The present invention also relates to methods for treating these diseases.
II. Description of the Related Art
Osseous tissue is composed of collagen, organic components fulfilling the clearances among the collagen, and bone matrix consisting of inorganic components comprising calcium and phosphorus as major constituents. Bones are continuously renewed by periodically repeating the osteogenesis by osteoblasts and the bone resorption by osteoclasts. Mechanical stimulations, various hormones, topical factors and the like influence the bone metabolism and the amount of the bone salt is maintained at about a certain level based on the balance of these factors. The representative bone disorder caused by the loss of this balance is osteoporosis. Osteoporosis is a systemic metabolic bone disorder which causes the decrease in the amount of the bones without associating chemical change of the bones, and in turn, adverse change of dynamic structure of the bones so as to show symptoms such as fracture of lumbar vertebra and femur, as well as pain in the waist and back.
On the other hand, bones are also important for the homeostasis of minerals. As a dysbolism of calcium, hypercalcemia accompanied by malignant tumors is known. Since the hypercalcemia is partly caused by the humoral factor produced by the tumor, the hypercalcemia is called humoral hypercalcemia of malignancy (HHM). Most of HHM shows hypercalcemia, hypophosphatemia, high level of CAMP in urine, reduction of threshold value of resorption of phosphate by renal tubule and the like, and presents symptoms including digestive disorders such as nausea and vomiting, and central nervous disorders such as easy feeling of fatigue, confusion and coma. The disorder rapidly proceeds and the symptoms are heavy.
As the substance causing the disorder, parathyroid hormone related protein (PTHrP) was recently isolated. This protein consists of 141 amino acids and has an amino acid sequence at its N-terminal region similar to that of parathyroid hormone (PTH).
Osteoclast activating factor (OAF) is also considered as a substance causing HHM. OAF is now considered identical with interleukin-1. Other known substances which promote the bone resorption include TNF-.alpha., TNF-.beta. and TGF-.alpha..
The treatment of HHM is basically carried out by co-employment of sufficient supplementation of fluid and Flomide (ectaric acid), and additionally, administration of calcitonin, glucocorticoid, indomethacin, mysramicin or the like is necessary. However, the therapeutic effect is small even if any of these methods is employed since the therapeutic effect is only temporary or the side effect must be taken into consideration.
The conventional treatment of osteoporosis is based on the promotion of osteogenesis and inhibition of bone resorption. Particularly, calcium formulations, estrogen, active vitamin D, calcitonin, Ipriflavon, bisphosphate are conventionally used for the treatment of osteoporosis. However, none of these is an effective therapeutic agent.